Dialysis membranes of cellulose for hemodialysis in the form of flat films, blown films or tubular threads have been known for some time and are the preferred materials for artificial kidneys. However, properties causing some unwanted side effects have not yet been eliminated.
A dialysis membrane for hemodialysis with reduced thrombogenic activity of cellulose with antithrombogenic compounds chemically bound thereto is known from West German No. 27 05 735, in which the dialysis membrane consists of two or more layers of a cellulose regenerated from cuoxam cellulose solutions. The two or more layers are obtained from separately supplied slits of a spinning nozzle or spinneret, wherein the cellulose layer adjacent the blood side consists entirely or partially of modified cellulose containing chemically bound anti-thrombogenic substances.
Further proposed in West German Laid-open Application No. 17 20 087, to reduce the dangers of blood coagulation, is reacting the polymer material of the membrane with an alkyl halide, then reacting the resulting material with an alkali salt of an antithrombogenic compound with cationic residue (e.g., heparin or a heparinoid compound). The possible alkyl halides include halogen alkyldialkylamines. Cellulose, primarily cellulose acetate, are among the possible polymers used for the membrane.
However, any antithrombogenic action of these known dialysis membranes is observed only if the degree of substitution of the modified cellulose is high (i.e., greater than at least 0.1) and a preliminary heparinization is carried out in a separate step with relatively high heparin concentrations (0.1 to 1 wt.% solutions).
Besides the fact that dialysis membranes made of synthetic or natural polymers, when used in artificial kidneys, can easily cause blood coagulation, which in turn is largely prevented by appropriate drug treatment, an additional problem often occurs with the dialysis membranes of regenerated cellulose, which heretofore could not be solved satisfactorily.
It has been demonstrated, for example, that a transient decrease in the number of leukocytes, known as leukopenia, can occur initially in dialysis treatment, when treating a kidney patient with regenerated cellulose-membrane dialyzers. Leukopenia denotes a decreased production of leukocytes (white blood cells) in the blood circulation. The average number of leukocytes (white blood cells) in humans is approximately 4000 to 12,000 cells/mm.sup.3. Leukopenia during dialysis is most prevalent 15 to 20 min after initiation of the treatment time, during which time neutrophils (i.e., leukocytes stainable with neutral or concurrently with acidic and basic dyes) can almost totally disappear. The leukocyte count gradually recovers within about an hour, to the initial value or possibly higher. If a new dialyzer is connected after the recovery of leukocytes, leukopenia, to a similar degree, will recur.
Cellulose membranes are responsible for noticeable leukopenia effects, and even if the clinical significance of the leukopenia has not been scientifically explained, there is the desire to design a dialysis membrane for hemodialysis which does not exhibit the leukopenia effect, without thereby affecting the other very desirable properties of dialysis membranes of regenerated cellulose.
In addition to leukopenia, noticeable complement activation has also been found to exist, in hemodialysis with membranes of regenerated cellulose. The complement system within the blood serum is a complex system of plasma enzymes, consisting of many components, which in various ways serve as defenses against injury caused by invading foreign cells (bacteria, etc.). If antibodies for attacking the invading organism are present, they can be activated complement-specifically via the antibody complex by antigenic structures found on foreign cells. In other cases, the activation of complements occurs via an alternate route by the specific surface features of the foreign cells. The system of complements is based on a multitude of plasma proteins. Following activation, these proteins interact in a specific order of sequence and in the end a cellulotoxic complex is formed that destroys the foreign cell.
Peptides, which induce inflammation symptons and occasionally may also have undesirable pathological consequences for the body, are released from separate components. It is assumed that the activation in the case of hemodialysis membranes of regenerated cellulose occurs via the alternate route.
Objectively, these complement activations can be shown to exist by finding the complement fragments C3a and C5a. The following reports are cited within this context: D. E. Chenoweth et al., Kidney International Vol. 24, pp. 764 ff, 1983, and D. E. Chenoweth, Asaio-Journal Vol. 7, pp. 44 ff, 1984.
Although the clinical significance of complement activation has not been explained, efforts have been made to eliminate the same in hemodialysis as much as possible.
These three factors, blood coagulation, leukopenia and complement activation are currently regarded as the three most critical parameters for biocompatibility of dialysis membranes. It is, therefore, the object of the present invention to make available a dialysis membrane, which clearly reduces the effects of complement activation and leukopenia, while simultaneously retaining the relatively beneficial properties of the cellulose membrane regarding blood coagulation.